Diarylamino-acetyl-aryl derivatives



United States Patent 3,143,568 DIARYLAMlNO-ACETYL-ARYL DERIVATIVES GuidoCavallini and Elena Massarani, Milan, Italy, as-

signors to Francesco Vismara S.p.A., Casatenovo (Como), Italy, a firm N0Drawing. Filed Jan. 16, 1962, Ser. No. 166,715 Claims priority,application Italy Jan. 25, 1961 7 Claims. (Cl. 260518) This inventionrelates to novel diarylamino-acetylaryl derivatives of the followingformula:

Formula I in which:

R represents hydrogen, methyl, halogen of atomic weight less than 80,preferably chlorine or bromine, nitro, methoxy, carboxy or carbethoxy, Rbeing preferably in the para position with respect to the amino group;and

R represents one of the following groups:

in which Y represents hydrogen, halogen of atomic weight less than 80,preferably chlorine or bromine, nitro, hydroxy, methoxy or R1 -0 OOHNil-Q 3,143,568 Patented Aug. 4, 1964 CO-OH in which R and R are asdefined above and Y represents hydrogen, chlorine, nitro, methoxy,hydroxy or Y represents hydrogen or and A represents oxygen, sulfur,sulfonyl, ethylene, methylene or vinylene.

The diarylamino-acetyl-aryl derivatives of this invention are preparedby reacting in the presence of a suitable solvent, a glyoxal of theformula:

Formula II 0 in which R represents one of the following groups:

in which A and R are as defined above and Y represents hydrogen, halogenof atomic weight less than 80, preferably chlorine or bromine, nitro,hydroxy, methoxy or another COCHO group, with an aromatic amine of theformula:

Formula III in which R is as defined above. The glyoxal may also bereacted as an addition derivative for example as the hydrate orhemiacetal.

The glyoxal starting materials are either known or can be preparedreadily for example by oxidation of corresponding methyl ketones Withselenium dioxide or by treating gem-dihalogen derivatives of the samemethyl ketone with an alkaline alcoholate and successive hydrolysis ofthe acetal thus obtained. The anhydrous glyoxals readily add Water oralcohol to give the corresponding hydrates and alcoholates. Many of theglyoxal starting As suitable solvents in the reaction to prepare thecompounds of this invention there may be used lower aliphatic alcoholsand also hydrocarbons, for example benzene and its homologues, hexane,cyclohexane or also solvents of the ether type such as tetrahydrofuran,dioxane and diethyl' ether. Particularly advantageous solvents areethanoL'isopropanol, tertiary butanol and benzene.

The reaction is carried out using approximately two moles of the aminefor every mole of the monoglyoxal or four moles of the amine for everymole of the bis- 7 glyoxal and operating at a temperature betweenambient temperature (about 25 C.) and 80 C. preferably between 5070 C.The reaction time can vary from about 30 minutes to about six hoursdepending upon the nature of the reagents and the temperature. Ingeneral, however, the reaction is practically complete after refluxingat 60 C. for about 4 hours. The diarylamino-acetyl-aryl derivativeseparates generally by cooling the reaction mixture and can thus beisolated by simple filtration. The product thus obtained is practicallypure and sometimes crystallizes with a molecule of the reaction solvent.The yield of the finalproduct is, optimal and can approach 90% oftheory.

The following examples illustrate the compounds of Example 1 A mixtureof 1.34 g. of phenylglyoxal, 1.86 g. of aniline and 60 cc. of anhydrousbenzene is heated at 60 C. for 4 hours. At the end of the reaction themixture is cooled slowly to yield' w,w-diphenylamino-acetophenone, whichthis invention and are not to be considered as limiting. 0 I

aniline and p-chloroaniline, there is obtained the correspendingderivatives w,w- [di-(4-nitrophenylamino) -acetophenone, M.P. 156 C. andw,w-[di-(4-chlorophenylam1- no)]-acetophenone, M.P. 120-122 C.

Example 2 Phenylglyoxal (1.34 g.) and 2.74 g. of p-aminobenzoic acid areheated at 60 C. for 2 hours in 30 cc. of tertiary butyl alcohol. Coolingseparates the crystalline product w,w [di (4 carboxyphenylamino)]acetophenone, M.P. 174-176 C.

Similarly, treating 0.01 mole of phenylglyoxal with 0.02 mole of ethylp-aminobenzoate there is obtained w,w- [di-(4-carbethoxyphenylamino)]-acetophenone, M.P. 144- 145 C. Example 3 Amixture of 1.34 g. of phenylglyoxal, 2.14 g. of p-toludine and 50cc. ofethanol is heated at 50 C. for 4 hours and then cooled slowly. Theprecipitate is w,w-[dl-(4- tolylamino)]-acetophenone, M.P. 11011l C.

4 Example 5 4-nitrophenylglyoxal (1.8 g., obtained from4-nitroacetophenone) and 2.76 g. of p-nitroaniline are heated for 6hours at 50 C. in cc. of benzene. Following the procedure of Example 1yields w,w-[di-(4'-nitrophenylamino)]-4-nitroacetophenone, M.P. 147-150"C.

Example 6 Following the procedure of Example 2, and treating in tertiarybutyl alcohol 1.8 g. of 4-nitrophenylglyoxal with 0.02 mole respectivelyof p-aminobenzoic acid and its ethyl ester there is obtained thefollowing derivatives,

'01,! [di (4 carboxyphenylamino)] 4 nitroacetophenone, M.P. 15916l Cland w,w-[di-(4'-carbethoxyphenylamino)]-4 nitroacetophenone, M.P. l03105C.

Example 7 Example 8 4 Following the procedure of Example 2 and treating4- methoxyphenylglyoxal with p-nitroaniline in tertiary butanol yieldsw,w-[di-(4'-nitrophenylamino)]-4-methoxyacetophenone, M.P. 161163 C.

Similarly 4-hydroxyphenylglyoxal and aniline yieldw,wdiphenylamino4-hydroxyacetophenone.

Example 9 A mixture of 2.1 g. of diphenylyl-4-glyoxal, 2.76 g. of

A p-nitroaniline and 20 cc. of tertiary butyl alcohol is heated at 60 C.for 4 hours. Cooling yields the product, 4-[di- (4' nitrophenylamino)]acetyl diphenyl, M.P. 166- 168 C.

Example 10 A mixture of 2.1 g. of diphenylyl-4-glyoxal, 2.74 g. ofp-aminobenzoic acid and 20 cc. of tertiary butyl alcohol is treated asin the preceding example. Cooling separates the product which afterfiltration, washing with ether and drying melts at 179-181 C. Analysisestablished that the product obtained is .4-[di-(4'-carboxyphenylamino)acetyl-diphenyl which crystallizes with one molecule of tertiary butylalcohol.

Carrying out the same reactionin benzene. instead .of

I tertiary butyl alcohol yields 4-[di-(4-carboxyphenyl Similarly,treating 0.01 mole of phenylglyoxal with I 0.02 mole of p-anisidineinethanol yields w,w [di (4-methoxyphenylamino) J-acetophenone, M.P. 118C.

Example 4 4-chlorophenylglyoxal (1.7 g.) and 2.74 g. of p-aminobenzoicacid are heated at 60 C. for 4 hours in 50 cc. of benzene. Following theprocedure of Example 1, there is obtained war[di-(4'-carboxyphenylamino)]-4-ch1oroacetophenone, M.P. 181 C. ISimilarly, there is prepared w,w-[di-(4'-carbethoxyphenylamino)]-4-chloroacetophenone, M.P. 147 C.

amino)]-acetyl-diphenyl, M.P. 176 C.

Using tetrahydrofuran as a solvent, the diamino derivative crystallizeswith one mole of solvent and theproduct thus obtained melts at 165 C, VV j Example 11 Example 12 A mixture of 2.43 g. ofdiphenylether-4-glyoxal hydrate, 2.66 g. of p-anisidine and 60 cc. ofethanol is heated at 50 C. for 5 hours. At the end of the reaction themixture is slowly cooled and the formed precipitate is filtered to g1ve4-[di-(4-methoxyphenylamino)l acetyl diphenylether, M.P. -94 C.

Example 13 A mixture of 2.59 g. of diphenylsulfide-4-glyoxal hydrate,2.66 g. of p-anisidine and 60 cc. of benzene is heated at 50 C. forhours. Cooling and filtering yields 4-[di- (4-methox'yphenylamino) l-acetyl-diphenylsulfide.

Example 14 A mixture of 2.55 g. of diphenylethane-4-glyoxal hydrate,2.65 g. of p-anisidine and 60 cc. of benzene is heated at 60 C. for 3hours. The cooled reaction mixture is filtered to yield4-[di-(4-methoxyphenylamino)]-acetyl diphenylethane.

Similarly, there is prepared4-[di-(4-methoxyphenylamino)]-acetyl-stilbene and 4-[di (4methoxyphenylamino) -acetyl-diphenylmethane.

Example 15 A mixture of 2.9 g. of diphenylsulfone-4-glyoxal hydrate,2.74 g. of p-aminobenzoic acid and 5 cc. of benzene is heated at 40 C.for 3 hours and then cooled to precipitate4-{di-(4'-carboxyphenylamino)] acetyl diphenylsulfone.

Similarly, there is prepared 4-[di-(4'-carboxyphenylamino)-acetyl-diphenylsulfoxide.

Example 16 A mixture of 2.1 g. of diphenylyl-Z-glyoxal, 2.76 g. ofp-nitroaniline and 20 cc. of benzene is heated at 60 C. for 4 hours.Cooling separates 2-[di-(4'-nitrophenylamino) l-acetyl-diphenyl.

Example 17 A mixture or" 2.43 g. of diphenylether-3-glyoxal hydrate,2.66 g. of p-anisidine and 50 cc. of benzene is heated for 6 hours at 45C. Cooling the mixture and filtering the formed product yields 3 [di (4'methoxyphenylamino) 1 -acetyl-diphenylether.

Example 18 Diphenylyl-4,4'-bisglyoxal dihydrate (3 g.) and 5.5 g. ofp-aminobenzoic acid are heated at 70 C. for 4 hours in 50 cc. ofbenzene. After this period, the reaction mixture is cooled slowly toyield a precipitate, 4,4-bis- Edi-(4- carb oxyphenyl amino) -acetyl]-diphenyl.

Similarly 4,4'-bisglyoxalylbenzene dihydrate and paminobenzoic acid arereacted to yield 4,4-bis-[di-(4- carb oxyphenyl amino) -acetyl]-benzene.

Example 20 A mixture of 3.18 g. of diphenylether-4,4'-bis-glyoxaldihydrate, g. of p-anisidine and 60 cc. of benzene is heated at 60 C.for 4 hours. Following the procedure of Example 19 yields4,4'-bis-[di-(4-methoxyphenylamino) -acetyl] -diphenylether.

Example 21 A mixture of 3.28 g. of diphenylethane -4,4-bis-glyoxaldihydrate, 5.5 g. of p-aminobenzoic acid and 60 cc. of benzene is heatedfor 3 hours at 70 C. and then cooled slowly. The precipitate is4,4-bis-[di-(4-carboxyphenylamino) -acetyl] -diphenylethane.

5 Example 22 Diphenylyl-2,2-bisglyoxal tetrahydrate (3.4 g.) and 4.3 g.of p-toluidine are heated at 50 C. for 4 hours in 60 cc. of benzene.From the reaction mixture separates after cooling a precipitate,2,2-bis-[di-(4-tolylamino)acety1]- diphenyl.

Example 23 Diphenylsulfone-4,4'-bisglyoxal dihydrate (3.66 g.) and 6.6g. of ethyl p-aminobenzoate in cc. of benzene are heated at 70 C. for 4hours. Cooling the mixture separates 4,4'-bis-[di-(4-carbethoxyphenylamino) -acetyll -diphenylsulfone.

Example 24 A mixture of cc. of ethanol, 5 g. of naphthyl-lglyoxal and7.2 g. of p-aminobenzoic acid is refluxed for about 90 minutes and thencooled to 25 C. and filtered. The product is washed with acetone andthen other to give l- [di- 4-carboxyphenylamino) ]-acetyl-naphthalene,M.P. C. (dec.) The structure is confirmed by infrared analysis.

Example 25 Naphthyl-Z-glyoxal hydrate (2 g.) and 2.74 g. ofpaminobenzoic acid are heated at 60 C. for 2 hours in 30 cc. of tertiarybutyl alcohol. Cooling separates the crystalline product 2[di-(4-carboxyphenylamino)]- acetyl-naphthaleue, M.P. 20l202 C.

Operating in a similar manner but using ethyl p-aminohenzoate in placeof the free acid yields 2-[di-(4'-carbethoxyphenylamino)]-acetyl-naphthalene.

Example 26 A mixture of 7.75 g. of selenium dioxide, 2 cc. of water and20 cc. of dioxane is heated at 70 C. while a solution of 10.2 g. ofl-acetyl-4-chloronaphthalene in 60 cc. of dioxane is dripped in. Themixture is refluxed for five hours, then filtered hot and partiallyevaporated. By vacuum distillation there is obtained4-chloronaphthyl-lglyoxal hydrate, B.P. 132133 C./0.05 mm. Hg.

Following the procedure of Example 25, 2.36 g. of4-chloronaphthyl-l-glyoxal hydrate and 2.74 g. of paminobenzoic acid arereacted to yield l-[di-(4-carboxyphenylamino)-acetyl-4-chloronaphthalene.

Example 27 Following the procedures herein described the followingcompounds are similarly prepared.

w,w- [di- (4'chlorophenylamino) -4-methoxyacetophenone,

w,w [di- 4-tolylamino) 1 -4-methoxyacetophenone,

w,w- [di- (4-carboxyphenylamino) ]-4-methoxyacetophenone,

w,a: [di- (4'-carbethoxyphenylamino) -4-methoxyacetophenone,

4- [di- (4'-carboxyphenylamino) -acetyl-diphenylethane,

4- [di- 4'-carboxyphenylarnino) -acetyl-diphenylether,

4- [di- (4-carboxyphenylamino) 1 -acetyl-diphenyl-sulfide,

and

4- [di- 4'-carbethoxyphenylamino) J-acetyl-diphenylsulfide.

What is claimed is: 1. A chemical compound of the formula:

NHQ

in which:

R is a member selected from the group consisting of hydrogen, methyl,chlorine, bromine, nitro, methoxy, carboxy and carbethoxy; and

R is a member selected from the group consisting of the followingformulas:

and

in which:

Y is a member selected from the group consisting of hydrogen, chlorine,bromine, nitro, hydroxy, methoxy and R1 HQ where R is as defined above;

S A is a member selected from the group consisting of oxygen, sulfur,sulfinyl, sulfonyl, methylene, ethylene and vinylene; and R is a memberselected from the group consisting of hydrogen, chlorine and bromine. 2.A chemical compound of the formula:

CO-OH References Cited in the file of this patent UNITED STATES PATENTSCavallini et al May 22, 1962

1. A CHEMICAL COMPOUND OF THE FORMULA: